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A Wonderful Christmas with Mysterious Oscillations

It has been known for many decades that budding yeast cells can
spontaneously synchronize their metabolism and cell division when
grown in continuous cultures. This synchrony is most commonly and
conveniently observed as oscillations in the oxygen consumption of the
culture that can last over many weeks, as long as the culture is fed
with fresh growth media. Yet the complexity of this mysterious
phenomenon has resisted scientific curiosity for many decades and
shifted it to the periphery of mainstream research.

My work on cell growth brought me to these mysterious oscillations,
and I became fascinated by them and their challenge. At the time, it
was suggested that their role is to separate DNA replication in time
from the periods of intense oxygen consumption and reactive oxygen
species production, and thus reduce the mutation rate. This sounded
simple and intuitively appealing, so I did not pay much attention to
the controversy in the literature. I just liked the appealing idea.
Yet, when I started synchronizing yeast in the lab and looking at my
own data, I could not reconcile them with restricting DNA to the low
oxygen consumption phase. After checking meticulously everything in my
experiments and not finding artifacts, I finally read carefully enough
the published evidence and found that it was consistent with my data
but could not convince me that DNA replication is sequestered away
from the phase of high oxygen consumption. Now that made the whole
phenomenon all that more mysterious and compelling to me. I really
wanted to understand these oscillations!

I analyzed all my data and came up with my own hypothesis, but that
was not enough; the complexity of the phenomenon could have misled me,
so I needed a direct experimental test, ideally in a simple system
that we understand well. It was very clear both from my data and data
from many other labs published over 4-5 decades that the metabolic
cycling in continuous cultures is correlated with partial cell
division cycle synchrony. Thus, my idea was to simply synchronize
cells with respect to their cell division cycle and measure oxygen
consumption. Measurements of oxygen consumption during the division
cycle were done in the 1960-1980s, but the data was from cells that
mostly ferment (a very different growth condition) and not nearly as
quantitative as what can be achieved nowadays.
After considering all methods for synchronizing the cell division
cycle of yeast, I decided to use a nutritional pulse as the most
physiological method with the fewest artifacts. Instead of producing
the intended cell division cycle synchrony, however, my experiments
resulted in metabolic cycling without cell division cycling! At first,
of course, that was a great surprise. Multiple repetitions of the
experiment turned the observation into an exciting finding. Doing the
sampling was time-consuming and demanding in the extreme, but I was so
eager to know what was happening that I spent Christmas Day of 2010
collecting samples, the ones that ultimate were used for our article.
It is still the longest, the happiest and the most exciting Christmas
Day I have had in my life.

The results of the experiments gave an answer that I find very
convincing. I felt we had learned something exciting, at least
incredibly exciting for me, and I wanted to share it with colleagues
who might be interested in it and incorporate their feedback before
we submitted our article for review. I was shocked by the emotional
responses that our work elicited, but that is a subject for another essay.

In retrospect, the work behind our PNAS article was a thrilling and
rewarding journey. It certainly did not resolve the whole mystery but
gave us insightful glimpses into the complexity of metabolic
regulation and a delightfully memorable Christmas Day, one that I
would love to repeat.